The present invention relates to a drug for treating a patient suffering from intermittent claudication and more specifically to a drug for treating a patient suffering from intermittent claudication caused by, in particular, peripheral circulatory disorders such as arteriosclerosis obliterans or thromboangiitis obliterans.
The intermittent claudication means a symptom in which the following two conditions are repeated: the difficulty of continuous walking due to the malaise and pains of the lower limb muscles caused after the locomotion of a constant distance and the alleviation of these symptoms or a condition ready for walking again after the rest for several minutes.
One of the causes thereof may be peripheral arterial occlusive disease induced by the vasculopathy such as arteriosclerosis obliterans, thromboangiitis obliterans, aortitis syndrome, Behcet""s disease and collagenosis. It would generally be recognized that the amount of blood required for the muscular motion is reduced to a relatively low level due to these peripheral circulatory disorders {the degree of oxygen saturation in tissues (tissue oxygen saturation) is reduced}, metabolites such as lactic acid are accumulated in the muscles to thus stimulate terminals of sensory nerves and thus it becomes difficult to continue walking due to the pain.
As drugs for treating a patient suffering from intermittent claudication, there have conventionally been used, for instance, pentoxifylline having an effect of improving the red blood cell deformability, anti-platelet agents and cilostazol as a vasodilator (the 71st American Heart Association in the United States, 1998, Lecture No. 58), but the effects of these drugs have been far from satisfactory.
This is because, there are some problems to be solved, for instance, those relating to methods for evaluating drug efficacy, methods for clinical diagnosis and the efficacy of these drugs. The conventional evaluation methods have relied on the length of the walking distance judged on the basis of the patient""s subjective findings, but these methods suffer from such a problem that they are inferior in the objectivity and reproducibility. Moreover, there has been known a method for determining the ratio of the blood pressure observed at the ankle joint to that observed at the brachial region using the Doppler method. However, the ratio is a value observed during the resting stage of a patient and therefore, this method is insufficient as a method for diagnosing the symptoms of the intermittent claudication observed during motions.
On the other hand, as a result of the investigation of patients suffering from intermittent claudication, it has been recognized that there is a good correlation between the oxyhemoglobin-recovery time and the time required for the recovery of the tissue oxygen saturation, which have recently been used, in clinic, for evaluating the efficacy of drugs for treating intermittent claudication and the degree of the seriousness of the disorder (KOMIYAMA Takashi et al., Therapeutic Research, 1996, Vol. 17, No. 4, pp. 213-215).
Accordingly, it is an object of the present invention to provide a drug useful in the treatment of a patient suffering from intermittent claudication and having high safety.
It is another object of the present invention to provide a drug useful for the production of a therapeutic agent for intermittent claudication.
It is a further object of the present invention to provide a method for treating a patient suffering from intermittent claudication.
The present inventors have established an animal model possessing pathema quite similar to that of intermittent claudication in clinic and improved the evaluation method and apparatus, have conducted various studies using the animal model and the method and apparatus, have found that a specific piperidine derivative known as a serotonin antagonist or an antiplatelet agent and disclosed in Japanese Un-Examined Patent Publication No. Hei 8-3135 show extremely high effect as compared with the conventionally known therapeutic agents for intermittent claudication and have thus completed the present invention.
According to an aspect of the present invention, there is thus provided a therapeutic agent for intermittent claudication, which comprises a piperidine derivative represented by the following general formula (1) or a salt thereof as an effective component: 
wherein n is an integer equal to 2 or 3, Y represents a hydrogen atom or a halogen atom, and X represents a formyl group, an acetyl group or a hydrogen atom.
According to another aspect of the present invention, there is provided the use of the foregoing piperidine derivative represented by the general formula (1) or a salt thereof in order to prepare a therapeutic agent for intermittent claudication.
According to a further aspect of the present invention, there is also provided a method for treating a patient suffering from intermittent claudication, which comprises the step of administering, to the patient, an intermittent claudication-remedy comprising, as an effective component, the foregoing piperidine derivative represented by the general formula (1) or a salt thereof.
In this connection, the compound according to the present invention is effective, in particular, when the intermittent claudication is caused due to peripheral circulatory disorders and further when the peripheral circulatory disorder is caused due to arteriosclerosis obliterans. Moreover, particularly effective is a compound of Formula (1) wherein n is 2, Y is a hydrogen atom and X is a formyl group, among others.